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1.
Artigo em Inglês | MEDLINE | ID: mdl-38723979
2.
Biomed Mater ; 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740053

RESUMO

This study aimed to investigate the effects of magnesium-doped bioactive glass (Mg-BG) on the mineralization, odontogenesis, and anti-inflammatory abilities of human dental pulp stem cells (hDPSCs). Mg-BG powders with different Mg concentrations were successfully synthesized via the sol-gel method and evaluated using X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, and transmission electron microscopy. Apatite formation was observed on the surfaces of the materials after soaking in simulated body fluid. hDPSCs were cultured with Mg-BG powder extracts in vitro, and no evident cytotoxicity was observed. Mg-BG induced alkaline phosphatase (ALP) expression and mineralization of hDPSCs and upregulated the expression of odontogenic genes, including those encoding dentin sialophosphoprotein, dentin matrix protein 1, ALP, osteocalcin, and runt-related transcription factor 2. Moreover, secretion of inflammatory cytokines (interleukin [IL]-4, IL-6, IL-8, and tumor necrosis factor-alpha) was substantially suppressed by Mg-BG. Collectively, the results of this study suggest that Mg-BG has excellent in vitro bioactivity and is a potential material for vital pulp therapy for inflamed pulps.

3.
Cell Genom ; 4(3): 100501, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38335956

RESUMO

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci.


Assuntos
Osteoporose , Sequências Reguladoras de Ácido Nucleico , Humanos , Fatores de Transcrição/genética , Osteoporose/genética , Cromatina/genética , Regiões Promotoras Genéticas/genética
4.
Ann Surg Oncol ; 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38334847

RESUMO

BACKGROUND: The prognosis of limited-stage small cell lung cancer (LS-SCLC) after surgery usually is estimated at diagnosis, but how the prognosis actually evolves over time for patients who survived for a predefined time is unknown. METHODS: Data on patients with a diagnosis of LS-SCLC after surgery between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. The 5-year conditional cancer-specific survival (CCSS) and conditional overall survival (COS) were calculated. RESULTS: This study analyzed 997 patients (555 women, 55.7%) with a median age, of 67 years (interquartile range [IQR], 60-73 years). The 5-year CCSS and COS increased from 44.7% and 38.3%, respectively, at diagnosis to 83.7% and 67.9% at 5 years after diagnosis. Although there were large differences with different stages (stages I, II, and III) at diagnosis (respectively 59.5%, 28.4%; 28.1% for CCSS and 50.6%, 24.8%, and 23.6% for COS), the gap decreased with time, and the rates were similar after 5 years (respectively 85.0%, 80.3%, and 79.4% for CCSS; 65.6%, 56.9%, and 61.3% for COS). The 5-year conditional survival for the patients who received lobectomy was better than for those who received sublobectomy or pneumonectomy. Multivariable analyses showed that only age and resection type were independent predictors for CCSS and COS, respectively, throughout the period. CONCLUSION: Conditional survival estimates for LS-SCLC generally increased over time, with the most significant improvement in patients with advanced stage of disease. Resection type and old age represented extremely important determinants of prognosis after a lengthy event-free follow-up period.

5.
Nat Commun ; 15(1): 1409, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360850

RESUMO

The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression.


Assuntos
Artrite , Estudo de Associação Genômica Ampla , Humanos , Estudo de Associação Genômica Ampla/métodos , Predisposição Genética para Doença/genética , Regulação da Expressão Gênica , Cromatina/genética , Membrana Sinovial , Artrite/genética , Polimorfismo de Nucleotídeo Único
6.
Technol Health Care ; 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38251080

RESUMO

BACKGROUND: The implementation of the rotation system in the Chinese medical industry has achieved significant results. OBJECTIVES: The present study aims to 1) explore the strengths, weaknesses, opportunities and challenges of rotational nursing department implementation and 2) provide references for developing nursing staff's competencies in leadership, performance evaluation, quality of care, communication in relationships and human resources. METHODS: A total of 16 rotational nursing department staff members from a tertiary tuberculosis specialist hospital in Beijing were interviewed, and the interview data were analysed using a strengths, weaknesses, opportunities and threats analysis and class analysis. RESULTS: The advantages of the rotational nursing department included: (1) stimulating the nursing staff's enthusiasm and creativity; (2) strengthening the communication and collaboration between departments; (3) improving the detailed management of nursing quality; and (4) enhancing the nursing staff's comprehensive abilities. The disadvantages included: (1) the design of the rotation programme focusing on practice; (2) a lack of personalisation; and (3) imperfect performance assessment of the rotating staff. Opportunities included: (1) deepening the connotation of nursing job management and (2) developing the construction of nursing discipline and the need for personal career development and value realisation. Threats included the lack of a sound rotation management model to draw on. CONCLUSION: A rotational nursing department is conducive to enhancing the competence of nursing staff in management positions and providing new ideas for hospitals to select and train nursing management talents. By taking full advantage of the benefits of vertical nursing management, designing personalised rotation training programmes, building a diversified learning and training platform and developing a positive performance incentive mechanism is recommended to fully engage the role of rotation in nursing management talent training.

7.
J Agric Food Chem ; 72(6): 2888-2897, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38294413

RESUMO

Olfaction plays indispensable roles in insect behavior such as host location, foraging, oviposition, and avoiding predators. Chemosensory proteins (CSPs) can discriminate the hydrophobic odorants and transfer them to the odorant receptors. Presently, CSPs have been identified in many insect species. However, their presence and functions remain unknown in Bactrocera dorsalis, a destructive and invasive insect pest in the fruit and vegetable industry. Here, we annotated eight CSP genes in the genome of B. dorsalis. The results of quantitative real-time polymerase chain reaction (RT-qPCR) showed that BdorCSP3 was highly expressed in the antennae. Molecular docking and in vitro binding assays showed that BdorCSP3 had a good binding ability to host volatiles methyl eugenol (ME, male-specific attractant) and ß-caryophyllene (potential female attractant). Subsequently, CRISPR/Cas9 was used to generate BdorCSP3-/- mutants. Electroantennograms (EAGs) and behavioral assays revealed that male mutants significantly reduced the preference for ME, while female mutants lost their oviposition preference to ß-caryophyllene. Our data indicated that BdorCSP3 played important roles in the perception of ME and ß-caryophyllene. The results not only expanded our knowledge of the olfaction perception mechanism of insect CSPs but also provided a potential molecular target for the control of B. dorsalis.


Assuntos
Percepção Olfatória , Sesquiterpenos Policíclicos , Receptores Odorantes , Tephritidae , Animais , Feminino , Simulação de Acoplamento Molecular , Tephritidae/fisiologia , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo
8.
Surg Endosc ; 38(2): 640-647, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38012439

RESUMO

BACKGROUND: Lymph node status is an important factor in determining preoperative treatment strategies for stage T1b-T2 esophageal cancer (EC). Thus, the aim of this study was to investigate the risk factors for lymph node metastasis (LNM) in T1b-T2 EC and to establish and validate a risk-scoring model to guide the selection of optimal treatment options. METHODS: Patients who underwent upfront surgery for pT1b-T2 EC between January 2016 and December 2022 were analyzed. On the basis of the independent risk factors determined by multivariate logistic regression analysis, a risk-scoring model for the prediction of LNM was constructed and then validated. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminant ability of the model. RESULTS: The incidence of LNM was 33.5% (214/638) in our cohort, 33.4% (169/506) in the primary cohort and 34.1% (45/132) in the validation cohort. Multivariate analysis confirmed that primary site, tumor grade, tumor size, depth, and lymphovascular invasion were independent risk factors for LNM (all P < 0.05), and patients were grouped based on these factors. A 7-point risk-scoring model based on these variables had good predictive accuracy in both the primary cohort (AUC, 0.749; 95% confidence interval 0.709-0.786) and the validation cohort (AUC, 0.738; 95% confidence interval 0.655-0.811). CONCLUSION: A novel risk-scoring model for lymph node metastasis was established to guide the optimal treatment of patients with T1b-T2 EC.


Assuntos
Neoplasias Esofágicas , Humanos , Metástase Linfática/patologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Excisão de Linfonodo , Linfonodos/cirurgia , Linfonodos/patologia
9.
Eur J Cancer Prev ; 33(2): 152-160, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37991237

RESUMO

BACKGROUND: There is still a lack of high-level clinical evidence and uniform conclusions on whether there are differences in lymph node metastasis (LNM) and prognosis between early esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). METHODS: Patients with surgically resected, histologically diagnosed, pT1 EAC or ESCC in the Surveillance, Epidemiology and End Results registries database from 2004 to 2015 were included. Multivariable logistic regression, Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the histology and LNM or prognosis. RESULTS: A total of 570 early esophageal cancer patients were included. The LNM rates were 13.8% and 15.1% for EAC and ESCC ( P  = 0.757), respectively. Multivariate logistic regression analysis showed no significant association between histological type and LNM (odds ratio [OR], 1.209; 95% CI, 0.538-2.715; P  = 0.646). Moreover, the prognosis of early EAC and ESCC was shown to be comparable in both multivariate Cox regression (hazard ratio [HR], 1.483; 95% CI, 0.699-3.150; P  = 0.305) and the multivariate competing risk model (subdistribution HR, 1.451; 95% CI, 0.628-3.354; P  = 0.383). After propensity score matching, there were no significant differences between early EAC and ESCC in terms of LNM (10.6% vs.18.2%, P  = 0.215), 5-year CSS (89.8% [95% CI, 81.0%-98.6%] vs. 79.1% [95% CI, 67.9%-90.3%], P  = 0.102) and 5-year cumulative incidence of CSS (10.2% [95% CI, 1.4%-19.0%] vs. 79.1% [95% CI, 9.7%-32.1%], P  = 0.124). CONCLUSION: The risk of LNM and prognosis of early ESCC and EAC are comparable, so the treatment choice for early esophageal cancer does not depend on the histologic type.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Esofagectomia , Humanos , Estadiamento de Neoplasias , Metástase Linfática , Prognóstico , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia
10.
ACS Infect Dis ; 9(12): 2482-2493, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38019707

RESUMO

ß-Lactam antibiotics are the mainstay for the treatment of staphylococcal infections, but their utility is greatly limited by the emergence and rapid dissemination of methicillin-resistant Staphylococcus aureus (MRSA). Herein, we evaluated the ability of the plant-derived monoterpene carvacrol to act as an antibiotic adjuvant, revitalizing the anti-MRSA activity of ß-lactam antibiotics. Increased susceptibility of MRSA to ß-lactam antibiotics and significant synergistic activities were observed with carvacrol-based combinations. Carvacrol significantly inhibited MRSA biofilms and reduced the production of exopolysaccharide, polysaccharide intercellular adhesin, and extracellular DNA and showed synergistic biofilm inhibition in combination with ß-lactams. Transcriptome analysis revealed profound downregulation in the expression of genes involved in two-component systems and S. aureus infection. Mechanistic studies indicate that carvacrol inhibits the expression of staphylococcal accessory regulator sarA and interferes with SarA-mecA promoter binding that decreases mecA-mediated ß-lactam resistance. Consistently, the in vivo experiment also supported that carvacrol restored MRSA sensitivity to ß-lactam antibiotic treatments in both murine models of bacteremia and biofilm-associated infection. Our results indicated that carvacrol has a potential role as a combinatorial partner with ß-lactam antibiotics to address MRSA infections.


Assuntos
Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Animais , Camundongos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/metabolismo , Antibióticos beta Lactam , Staphylococcus aureus , Monobactamas , Biofilmes , Catéteres
11.
MedComm (2020) ; 4(4): e345, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37576863

RESUMO

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

12.
Am J Hum Genet ; 110(8): 1266-1288, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37506691

RESUMO

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.


Assuntos
Resistência à Insulina , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Fatores de Transcrição/genética , Cromatina/genética , Fenótipo , Elementos Facilitadores Genéticos/genética
13.
BMC Med ; 21(1): 271, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37491271

RESUMO

BACKGROUND: Stroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain. METHODS: We performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke. Summary data of 587 brain IDPs (up to 33,224 individuals) from the UK Biobank and five stroke types (sample size range from 301,663 to 446,696, case number range from 5,386 to 40,585) from the MEGASTROKE consortium were used. RESULTS: Forward MR indicated 14 IDPs belong to projection fibers or association fibers were associated with stroke. For example, higher genetically determined mean diffusivity (MD) in the right external capsule was causally associated with an increased risk of small vessel stroke (IVW OR = 2.76, 95% CI 2.07 to 3.68, P = 5.87 × 10-12). Reverse MR indicated that genetically determined higher risk of any ischemic stroke was associated with increased isotropic or free water volume fraction (ISOVF) in body of corpus callosum (IVW ß = 0.23, 95% CI 0.14 to 0.33, P = 3.22 × 10-7). This IDP is a commissural fiber and it is not included in the IDPs identified by forward MR. CONCLUSIONS: We identified 14 IDPs with statistically significant evidence of causal effects on stroke or stroke subtypes. We also identified potential causal effects of stroke on one IDP of commissural fiber. These findings might guide further work toward identifying preventative strategies at the brain imaging levels.


Assuntos
Análise da Randomização Mendeliana , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/genética , Encéfalo/diagnóstico por imagem , Fenótipo , Neuroimagem , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único
14.
JHEP Rep ; 5(7): 100763, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37333974

RESUMO

Background & Aims: Immunotherapy is an option for the treatment of advanced biliary tract cancer (BTC), although it has a low response rate. In this post hoc analysis, we investigated the predictive value of an immuno-genomic-radiomics (IGR) analysis for patients with BTC treated with camrelizumab plus gemcitabine and oxaliplatin (GEMOX) therapy. Methods: Thirty-two patients with BTC treated with camrelizumab plus GEMOX were prospectively enrolled. The relationship between high-throughput computed tomography (CT) radiomics features with immuno-genomic expression was tested and scaled with a full correlation matrix analysis. Odds ratio (OR) of IGR expression for objective response to camrelizumab plus GEMOX was tested with logistic regression analysis. Association of IGR expression with progression-free survival (PFS) and overall survival (OS) was analysed with a Cox proportional hazard regression. Results: CT radiomics correlated with CD8+ T cells (r = -0.72-0.71, p = 0.004-0.047), tumour mutation burden (TMB) (r = 0.59, p = 0.039), and ARID1A mutation (r = -0.58-0.57, p = 0.020-0.034). There was no significant correlation between radiomics and programmed cell death protein ligand 1 expression (p >0.96). Among all IGR biomarkers, only four radiomics features were independent predictors of objective response (OR = 0.09-3.81; p = 0.011-0.044). Combining independent radiomics features into an objective response prediction model achieved an area under the curve of 0.869. In a Cox analysis, radiomics signature [hazard ratio (HR) = 6.90, p <0.001], ARID1A (HR = 3.31, p = 0.013), and blood TMB (HR = 1.13, p = 0.023) were independent predictors of PFS. Radiomics signature (HR = 6.58, p <0.001) and CD8+ T cells (HR = 0.22, p = 0.004) were independent predictors of OS. Prognostic models integrating these features achieved concordance indexes of 0.677 and 0.681 for PFS and OS, respectively. Conclusions: Radiomics could act as a non-invasive immuno-genomic surrogate of BTC, which could further aid in response prediction for patients with BTC treated with immunotherapy. However, multicenter and larger sample studies are required to validate these results. Impact and implications: Immunotherapy is an alternative for the treatment of advanced BTC, whereas tumour response is heterogeneous. In a post hoc analysis of the single-arm phase II clinical trial (NCT03486678), we found that CT radiomics features were associated with the tumour microenvironment and that IGR expression was a promising marker for tumour response and long-term survival. Clinical trial number: Post hoc analysis of NCT03486678.

15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 31(3): 927-930, 2023 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-37356963

RESUMO

Most hematological tumors have high-grade malignancy and low cure rate, requiring new molecular markers for detection and evaluation. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed-loop structures, which participate in gene transcription and translation by binding to microRNAs and proteins. In recent years, with the deepening research on circRNAs, circRNAs have been found to play an important role in hematological malignancies. In this review, the latest research progress on the function and molecular mechanism of circRNAs in hematological malignancies was systematically summarized, and it was found that circRNAs may be potential new biomarkers and therapeutic targets in hematological malignancies.


Assuntos
Neoplasias Hematológicas , MicroRNAs , Neoplasias , Humanos , RNA Circular , MicroRNAs/genética , Neoplasias Hematológicas/genética , Biomarcadores
16.
Eur Heart J ; 44(29): 2746-2759, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37377116

RESUMO

AIMS: The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. METHODS AND RESULTS: Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans. CONCLUSION: The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66Shc-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.


Assuntos
Sirtuína 2 , Remodelação Vascular , Camundongos , Humanos , Animais , Idoso , Sirtuína 2/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento , Camundongos Knockout
17.
Am J Hum Genet ; 110(4): 625-637, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36924774

RESUMO

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.


Assuntos
Artrite Reumatoide , Sinoviócitos , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proliferação de Células/genética , Células Cultivadas , Cromossomos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Proteínas Repressoras/genética , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Proteína 2 Relacionada a Actina/metabolismo
18.
EBioMedicine ; 87: 104418, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36584593

RESUMO

Metabolism regulates cardiovascular biology through multiple mechanisms, including epigenetic modifications. Over the past two decades, experimental and preclinical studies have highlighted the critical roles of histone modifications in cardiovascular development, homeostasis, and diseases. The widely studied histone acetylation is critical in cardiovascular biology and diseases, and inhibitors of histone deacetylases show therapeutic values. In addition to lysine acetylation, a series of novel non-acetyl lysine acylations have recently been recognized. These non-acetyl lysine acylations have been demonstrated to have physiological and pathological functions, and recent studies have analyzed the roles of these non-acetyl lysine acylations in cardiovascular biology. Herein, we review the current advances in the understanding of non-acetyl lysine acylations in cardiovascular biology and discuss open questions and translational perspectives. These new pieces of evidence provide a more extensive insight into the epigenetic mechanisms underlying cardiovascular biology and help assess the feasibility of targeting acylations to treat cardiovascular diseases.


Assuntos
Histonas , Lisina , Humanos , Acetilação , Histonas/metabolismo , Lisina/metabolismo , Acilação , Processamento de Proteína Pós-Traducional , Biologia
19.
Neural Regen Res ; 18(1): 162-169, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35799537

RESUMO

We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique. Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury; as a result, in this study, we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration. First, in an in vitro biomimetic microenvironment, we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells. We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells. The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique. Compared with epithelium sutures and small gap sleeve bridging alone, the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.

20.
J Infect Dev Ctries ; 17(12): 1761-1768, 2023 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-38252728

RESUMO

INTRODUCTION: The objective of this study was to investigate the willingness of patients with tuberculosis (TB) to use mobile medical services (mHealth) and its influencing factors, so as to provide theoretical guidance for optimizing the TB mobile medical platform and improve the willingness of patients to use mHealth. METHODOLOGY: In this cross-sectional study, convenience sampling method was used to investigate patients with TB from the outpatient clinics of two TB specialized hospitals (Beijing Thoracic Tumor and Tuberculosis Hospital and Tuberculosis Prevention and Treatment Hospital of Shaanxi Province) from January to June 2021 using a self-designed questionnaire. RESULTS: Out of 231 patients, only 90 (38.96%) were aware of mHealth services, and 63 (27.27%) had used mHealth services. Among the 63 patients who had used mHealth services, the proportion of mobile medical forms based on WeChat platform was 74.89%. Patients' willingness to use mHealth was scored (11.49 ± 2.53). Univariate analysis showed that the scores of patients' willingness to use mHealth differed by gender and the different ways of affording healthcare (p < 0.05). Regression analysis showed that the influencing factors of willingness to use mHealth in patients with TB included attitude towards use (0.750), health beliefs (0.091) and social impact (0.169) (adjusted R2 = 0.781, p < 0.001). CONCLUSIONS: Patients' awareness of the advantages of the new medical model needs to be improved. Optimized design can improve the willingness of patients to use mHealth services and improve the role of mHealth in patient management.


Assuntos
Telemedicina , Tuberculose , Humanos , Estudos Transversais , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle , Instituições de Assistência Ambulatorial , Inquéritos e Questionários
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